SPP1 (secreted phosphoprotein 1)

2008-11-01   Lígia R Rodrigues 

IBB - Institute for Biotechnology, Bioengineering, Centre of Biological Engineering, Universidade do Minho, 4710-057 Braga, Portugal





Genes encompassed within a 600 kb region on human chromosome 4 encode several noncollageneous bone and dentin proteins. They include osteopontin, bone sialoprotein, dentin matrix protein I, and dentin sialophosphoprotein, all of which have been categorized as members of the small integring-binding ligand N-linked glycoprotein (SIBLING) family-related proteins. The 4 proteins are somewhat similar being secreted, sialylated, phosphorylated, and acidic in nature.
Atlas Image
The gene structure of human osteopontin. Exons are boxed, filled boxes are coding regions and open boxes are untranslated regions.


- Osteopontin is encoded by a single copy gene located on the human chromosome 4; 7 exons.
- Codon triplets are not interrupted by introns, and consequently, exon skipping will not affect the codon triplets in the remaining exons.
- The human gene sequence spans ~9 kb and the open reading frame consists of 942 nucleotides from the start codon (in exon 2) to the stop codon (in exon 7).


- The 5-untranslated region includes exon 1, which starts a transcription initiation site (AGC).
- The 3-untranslated region consists of the last part of exon 7, which includes three potential polyadenylation attachment signals (AATAA).
- Exon 2 encodes the signal peptide and the first two amino acids in the mature protein.
- Exon 3 and 5, the two characteristic Ser-Ser-Glu-Glu phosphorylation sequences.
- Exon 4, the two transglutaminase-reactive glutamine residues.
- Exon 6, the aspartic-rich sequence.
- Exon 7 is the largest exon encoding approzimately half of the proteins including the RGD motif and the central thrombin cleavage site.
- There are 3 transcripts for osteopontin splice variants that are OPN-a, OPN-b and OPN-c. Alternative splicing occurs in a region of the molecule that is upstream of the central integrin binding domain and the C-terminal CD44 binding domain. OPN-b lacks exon 5 and OPN-c lacks exon 4.
- Transcriptional regulation is complex and involves multiple pathways including AP-1, Myc, v-Src, RunX/CBF, TGF-B/BMPS/Smad/Hox and Wnt/b-catenin/APC/GSK-3b/Tcf-4.



Osteopontin serves as a substrate for thrombin and matrix metalloproteinases (MMP2, MMP3, MMP7, MMP9 and MMP12), can bind to the extracellular matrix proteins fibronectin and collagen, and interacts with integrins alphaV (beta1, beta2 or beta5) and (alpha4, alpha5, alpha8 or alpha9) beta1 surface receptors through an Arg-Gly-Asp (RGD) sequence.
Secreted phosphoprotein 1 (or osteopontin) was identified with 7 protein interactions: ITGAV, IGFBP5, PDLIM7, CD44, ITGA5, CTNNBL1, SGTA.
Atlas Image
Structure of human osteopontin protein indicating selected structural domains.


- Recommended name: osteopontin.
- Osteopontin is 314 amino acids in length.
- The molecular weight of osteopontin and associated isoforms are measured between 41 and 75 kDa. Post-translational modifications leading to cell-type and condition-specific variations may account for this variability in molecular weight.
- Osteopontin is extremely hydrophilic with a low isoelectric point (3.5).
- It displays an unusual amino acid composition with 42 serine, 48 aspartic acid and 27 glutaminc acid residues. It is important to notice that 27 out of the 42 serine serine residues are phosphorylated.
- The predicted secondary structure of osteopontin consists of eight alpha-helices and six beta-sheet segments.
- Strutural domains:
  • Aspartate domain - amino acid sequence Asp86-Asp89 - binds hydroxyapatite,
  • RGD sequence - amino acid sequence Arg159-Asp159 - binds alphaVbeta3, alphaVbeta1, alphaVbeta5 and alpha5beta1 integrins,
  • SVVYGLR sequence - amino acid sequence Ser162-Arg168 - binds alpha9beta1 and alpha1beta1 integrins,
  • Thrombin cleavage site - amino acid sequence Arg168-Ser169 - displays RGD sequence,
  • Calcium binding domain - amino acid sequence Asp216-Ser228 - calcium binding,
  • Heparin binding domain - amino acid sequence Asp290-Ile305 - mediates CD44v3 binding.
    - Post-translational modifications:
  • Extensively phosphorylated on clustered serine residues,
  • N- and O-glycosylated.
  • Expression

    Osteopontin is expressed by cells in a variety of tissues, including bone, dentin, cementum, hypertrophic cartilage, kidney, brain, bone-marrow-derived metrial gland cells, vascular tissues and cytotrophoblasts of the chorionic villus in the uterus and decidua, ganglia of the inner ear, brain cells and specialized epithelia found in mammary, salivary, and sweat glands, in bile and pancreatic ducts, and in distal renal tubules and in the gut, as well as in activated macrophages and lymphocytes.
    Cell types which express osteopontin: osteoclasts, osteoblasts, kidney, breast and skin epithelial cells, nerve cells, vascular smooth muscle cells and endothelial cells. Activated immune cells (T-cells, NK cells, macrophages and Kupfter cells) also express osteopontin.


    It is predominantly secreted but its intracellular form has also been described.


    - Binds tightly to hydroxyapatite. Appears to form an integral part of the mineralized matrix. Probably important to cell-matrix interaction.
    - Acts as a cytokine involved in enhancing production of interferon-gamma and interleukin-12 and reducing production of interleukin-10 and is essential in the pathway that leads to type I immunity.
    - Participates in bone remodelling, inflammation, cancer and immunity to infection disease.
    - Regulates the formation and growth of calcium phosphate and oxalate crystals.
    - Is involved in cell attachment and signalling through integrins.
    - Is involved in cell attachment and signalling through CD44.


    The amino acid sequence of osteopontin is nowadays available for several species, such as rat, mouse, human, pig, rabbit and cow. The referenced mammalian osteopontin sequences are identical in ~33% of the residues, and in addition, many similar amino acids are conserved between the sequences. Identical residues are scattered in clusters. More specifically, the larger clusters are located in the hydrophobic leader sequence (the first 16 residues), in a potential site for N-linked glycosylation, and in several sites for O-linked glycosylation and phosphorylation. A stretch of consecutive aspartic acid residues was also found in all species, as well as a cell attachment RGD motif almost immediately followed by a thrombin cleavage site.

    Implicated in

    Entity name
    Multiple cancers
    The ability of osteopontin to interact with a diverse range of factors including cell surface receptors (integrins, CD44), secreted proteases (matrix metalloproteinases, urokinase plasminogen activator) and growth factor/receptor pathways (TGFalpha/EGFR, HGF/MET) is central to its role in malignancy.
    Changes in gene expression implies alterations in cell properties involved in malignancy such as adhesion, migration, invasion, enhanced tumour survival, tumour angiogenesis, and metastasis.
    Multiple cancers such as breast, thyroid, cervical, prostate, lung, gastric, liver and colon.
    At present, it is fully accepted that osteopontin expressed by tumour cells alters their malignant properties, specifically by affecting their ability to grow, invade, and metastatize. However, it is important to notice that osteopontin is expressed both in normal and malignant tissues. Recent studies suggest that osteopontin levels in the blood or tumours of patients with cancer may provide useful clinical information on patient prognoses.
    Elevated osteopontin expression correlate with tumour invasion, progression or metastasis in multiple cancers (thyroid, cervical, breast, prostate, lung, gastric, liver and colon). Osteopontin expression is associated with disease progression in patients, with higher levels of osteopontin produced by cancer cells associated with a poorer patient survival.
    Osteopontin is believed to be an effector of activated oncogenes functioning to facilitate tumour growth and metastasis.


    Pubmed IDLast YearTitleAuthors
    150999462004Utility of osteopontin as a biomarker in recurrent epithelial ovarian cancer.Brakora KA et al
    14215731992Expression and distribution of osteopontin in human tissues: widespread association with luminal epithelial surfaces.Brown LF et al
    80800431994Osteopontin expression and distribution in human carcinomas.Brown LF et al
    26983131989The nature and significance of osteopontin.Butler WT et al
    181723072008Osteopontin promotes vascular endothelial growth factor-dependent breast tumor growth and angiogenesis via autocrine and paracrine mechanisms.Chakraborty G et al
    158694642005Post-translationally modified residues of native human osteopontin are located in clusters: identification of 36 phosphorylation and five O-glycosylation sites and their biological implications.Christensen B et al
    82623321993Osteopontin: a protein with diverse functions.Denhardt DT et al
    118992362001The functional and clinical roles of osteopontin in cancer and metastasis.Furger KA et al
    184709112008Downregulation of osteopontin contributes to metastasis suppression by breast cancer metastasis suppressor 1.Hedley BD et al
    79452491994Cloning and characterization of the human osteopontin gene and its promoter.Hijiya N et al
    27264701989The cDNA and derived amino acid sequence for human osteopontin.Kiefer MC et al
    119268912002Osteopontin as a potential diagnostic biomarker for ovarian cancer.Kim JH et al
    118347672002Osteopontin--a molecule for all seasons.Mazzali M et al
    179606162008Osteopontin-c is a selective marker of breast cancer.Mirza M et al
    94253201997The role of osteopontin in tumorigenesis and metastasis.Oates AJ et al
    183784372008Genetic networks of cooperative redox regulation of osteopontin.Partridge CR et al
    93421841997Osteopontin expression in mammary gland development and tumorigenesis.Rittling SR et al
    175486692007The role of osteopontin in tumor progression and metastasis in breast cancer.Rodrigues LR et al
    110216312000Osteopontin.Sodek J et al
    177218862007Osteopontin overexpression in breast cancer: knowledge gained and possible implications for clinical management.Tuck AB et al
    180498632008Osteopontin: regulation in tumor metastasis.Wai PY et al
    118256872001The metastasis gene osteopontin: a candidate target for cancer therapy.Weber GF et al

    Other Information

    Locus ID:

    NCBI: 6696
    MIM: 166490
    HGNC: 11255
    Ensembl: ENSG00000118785


    dbSNP: 6696
    ClinVar: 6696
    TCGA: ENSG00000118785


    Gene IDTranscript IDUniprot

    Expression (GTEx)



    PathwaySourceExternal ID
    Focal adhesionKEGGko04510
    ECM-receptor interactionKEGGko04512
    Toll-like receptor signaling pathwayKEGGko04620
    Focal adhesionKEGGhsa04510
    ECM-receptor interactionKEGGhsa04512
    Toll-like receptor signaling pathwayKEGGhsa04620
    PI3K-Akt signaling pathwayKEGGhsa04151
    PI3K-Akt signaling pathwayKEGGko04151
    Signal TransductionREACTOMER-HSA-162582
    Signaling by PDGFREACTOMER-HSA-186797
    Extracellular matrix organizationREACTOMER-HSA-1474244
    Degradation of the extracellular matrixREACTOMER-HSA-1474228
    Integrin cell surface interactionsREACTOMER-HSA-216083
    Apelin signaling pathwayKEGGhsa04371

    Protein levels (Protein atlas)

    Not detected


    Entity IDNameTypeEvidenceAssociationPKPDPMIDs
    PA443434Arthritis, RheumatoidDiseaseMultilinkAnnotationassociated24448344


    Pubmed IDYearTitleCitations
    126404472003Predicting hepatitis B virus-positive metastatic hepatocellular carcinomas using gene expression profiling and supervised machine learning.239
    117210592001The influence of the proinflammatory cytokine, osteopontin, on autoimmune demyelinating disease.207
    246074072014Osteopontin-CD44 signaling in the glioma perivascular niche enhances cancer stem cell phenotypes and promotes aggressive tumor growth.152
    219532992012Identification of osteopontin as a novel marker for early hepatocellular carcinoma.102
    256586392015Glioma-associated microglia/macrophages display an expression profile different from M1 and M2 polarization and highly express Gpnmb and Spp1.99
    211780992011SPP1 genotype is a determinant of disease severity in Duchenne muscular dystrophy.90
    155014632004The role of Osteopontin in tumor metastasis.87
    154946842004Role of osteopontin in adhesion, migration, cell survival and bone remodeling.85
    195974692009Osteopontin induces angiogenesis through activation of PI3K/AKT and ERK1/2 in endothelial cells.85
    199131212009Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.85


    Lígia R Rodrigues

    SPP1 (secreted phosphoprotein 1)

    Atlas Genet Cytogenet Oncol Haematol. 2008-11-01

    Online version: http://atlasgeneticsoncology.org/gene/42379/spp1-(secreted-phosphoprotein-1)